The majority of currently available antidepressants can be classified in 3 classes:                1) monoamine oxidase inhibitors (MAOIs),        2) biogenic amine neurotransmitter [serotonin (5-HT), norepinephrine (NE) and dopamine (DA)] transporter reuptake blockers, and        3) modulators, especially blockers of one or more of the 5-HT and/or NE receptors.        
Since depression is associated with a relative deficiency of the biogenic amines, the use of 5-HT and/or NE-receptor blockers (i.e. 5-HT and or NE-antagonist's) have not proven very successful in the treatment of depression and anxiety and the preferred and currently most efficient treatments are based on the enhancement of 5-HT and/or NE neurotransmission by blocking their reuptake back from the synaptic cleft (Slattery, D. A. et al., “The evolution of antidepressant mechanisms”, fundamental and Clinical pharmacology, 2004, 18, 1-21; Schloss, P. et al, “new insights into the mechanism of antidepressant therapy”, Pharmacology and therapeutics, 2004, 102, 47-60).
For years monoamine reuptake inhibition has been studied for treatment of depression, i.e. in particular the monoamines serotonin (5-HT), norepinephrine (NE) and dopamine (DA).
Selective serotonin reuptake inhibitors (hereinafter referred to as SSRIs) have become first choice therapeutics in the treatment of depression, certain forms of anxiety and social phobias, because they generally are effective, well tolerated, and have a favourable safety profile compared to the classic tricyclic antidepressants. Drugs claimed to be SSRIs are for example fluoxetine, sertraline and paroxetine.
However, clinical studies on depression indicate that non-response to the known SSRIs is substantial, up to 30%. Another, often neglected, factor in antidepressant treatment is compliance, which has a rather profound effect on the patient's motivation to continue pharmacotherapy. First of all, there is generally a delay in therapeutic effect of the SSRIs. Sometimes symptoms even worsen during the first weeks of treatment. Secondly, sexual dysfunction is generally a side effect common to SSRIs. Without addressing these problems, real progress in the pharmacotherapy of depression and anxiety disorders is not likely to happen. Accordingly, there is a need for the development of compounds capable of improving the treatment of depression and other serotonin related diseases.
A newer strategy has been the development of dual re-uptake inhibitors, e.g., the combined effect of serotonin reuptake inhibition and norepinephrine (norepinephrine is also named noradrenaline, NA) reuptake inhibition on depression is explored in clinical studies of compounds such as Duloxetine (Wong, “Duloxetine (LY-248686): an inhibitor of serotonin and noradrenaline uptake and an antidepressant drug candidate”, Expert Opinion on Investigational Drugs, 1998, 7, 10, 1691-1699) and Venlafaxine (Khan-A et al, 30 “Venlafaxine in depressed outpatients”, Psychopharmacology Bulletin, 1991, 27, 141-144). Compounds having such duel effect are also named SNRIs, “serotonin and noradrenaline reuptake inhibitors”, or NSRIs, “noradrenaline and serotonin reuptake inhibitors”.
Since treatment with the selective NE reuptake inhibitor reboxetine has been shown to stimulate 5-HT neurons and mediate the release of 5-HT in the brain (Svensson, T. et al, J. Neural. Transmission, 2004, 111, 127) there might be a synergistic advantage using SNRI's in the treatment of depression or anxiety.
The use of SNRI's have been shown in clinical studies to have a beneficial effect on pain (e.g. Fibromyalgia syndrome, overall pain, back pain, shoulder pain, headache, pain while awake and during daily activities) and especially pain associated with depression (Berk, M. Expert Rev. Neurotherapeutics 2003, 3, 47-451; Fishbain, D. A., et al. “Evidence-based data from animal and human experimental studies on pain relief with antidepressants: A structured review” Pain Medicine 2000 1:310-316).
SNRI's have also been shown in clinical studies to have a beneficial effect in attention deficit hyperactivity disorder (ADHD) (N. M. Mukaddes; Venlafaxine in attention deficit hyperactivity disorder, European Neuropsychopharmacology, Volume 12, Supplement 3, October 2002, Page 421).
Furthermore, SNRI's have been shown to be effective for the treatment of stress urinary incontinence (Dmochowski R. R. et al. “Duloxetine versus placebo for the treatment of North American women with stress urinary incontinence”, Journal of Urology 2003, 170:4, 1259-1263.)
Furthermore, Axford L. et al. describe the development of triple 5-HT, NE and DA re-uptake inhibitors for treatment of depression. (2003, Bioorganic & Medical Chemistry Letters, 13, 3277-3280: “Bicyclo[2.2.1.]heptanes as novel triple re-uptake inhibitors for the treatment of depression”). Wellbutrin (bupropion) which has DA re-uptake activity in vitro and in vivo, show antidepressant efficacy. Other combination studies have indicated that addition of some affininity at the DA uptake site may have some clinical benefit (Nelson, J. C. J. Clin. Psychiatry 1998, 59, 65; Masand, P. S. et al. Depression Anxiety 1998, 7, 89; Bodkin, J. A et al. J. Clin. Psychiatry 1997, 58, 137).
The present invention provides 2-(1H-indolylsulfanyl)-benzyl amine derivatives, formula I, which are serotonin reuptake inhibitors. In particular, the invention provides compounds possessing the combined effect of serotonin reuptake inhibition and norepinephrine reuptake inhibition. Furthermore, some of the compounds are also triple 5-HT, NE and DA re-uptake inhibitors.
Diphenyl sulphides of formula (XVI) and variations thereof have been disclosed as serotonin re-uptake inhibitors and have been suggested for use in treatment of depression, cf. e.g. U.S. Pat. No. 5,095,039, U.S. Pat. No. 4,056,632, EP 396827 A1 and WO 9312080. EP 402097 describes halogen substituted diphenylsulfides claimed to be selective serotonin inhibitors for treatment of depression. Likewise WO 9717325 discloses derivatives of N,N-dimethyl-2-(arylthio)benzylamine claimed to be selective serotonin transport inhibitors and suggest their use as antidepressants. J. Jilek et al., 1989, Collect. Czeck Chem. Commun., 54, 3294-3338 also discloses various derivatives of diphenyl sulphides, “phenyl-thio-benzylamines” as antidepressants. Furthermore, diphenyl sulphides are also disclosed in U.S. Pat. No. 3,803,143 and claimed useful as antidepressant.
Several publications relates to the use of derivatives of diphenyl sulphides as “radiopharmaceuticals” for imaging SERT by SPECT or PET imaging, e.g. “S. Oya et al. J. Med Chem. 2002, 45, 4716-4723” and “S. Oya et al. J. Med. Chem. 42, 3, 333-335”. P. Emond et al (J. Med. Chem (2002) 45, 1253-1258) and “S. Oya et al. (J. Med. Chem. 42, 3, 333-335) further test and discuss substituted “diphenyl sulfides” as selective serotonin tranporter ligands relative to dopamine and norepinephrine transporters (DAT, NET) with measurements of vitro affinities at the dopamine, serotonin, and norepinephrine transporters.
WO 0066537 also discloses certain derivatives of diphenyl sulphides claimed to be have higher selectivity for SERT over NET and DAT.
U.S. Pat. No. 4,018,830 and U.S. Pat. No. 4,055,665 discloses “phenylthioaralkylamines” and “2-phenylthiobenzylamines” represented structurally as “Ar1-S-Ar2 in which Ar1 is a phenylakyl amine substituent and Ar2 is a substituted or unsubstituted homocyclic or heterocyclic ring of from 5-6 atoms, such as an aromatic ring, a heteroaromatic ring”. The compounds are claimed to be useful for preventing “cardiac arrhythmias”.
K. Sindelar et al., “Collection of Czechoslovak Chemical Communications, (1991), 56(2), 449-58, by K. Sindelar et al” disclose variations of compounds of formula (XVI) in which one of the rings is substituted with a thiophene ring with test for selectivity as 5-HT re-uptake inhibitor and NA re-uptake inhibitor, respectively, for use as antidepressants.
U.S. Pat. No. 6,596,741 B2 and U.S. Pat. No. 6,436,938 B1 and U.S. Pat. No. 6,410,736 B1 disclose biaryl ether derivates (XVII) reported to inhibit reuptake of monoamines, e.g. serotonin, dopamine and/or norepinephrine.
None of the above references disclose compounds comprising an indole group like the indolyl-sulfanyl benzyl amines of the present invention.